Transdermal delivery of pharmaceutical agents

ABSTRACT

A method of administering a pharmaceutical agent to the circulatory system through the skin of a mammal may include the steps of loading a pharmaceutical agent in a transdermal patch, applying the transdermal patch to the skin of the mammal and releasing the pharmaceutical agent into the circulatory system at a rate of at least 0.001 micrograms per hour up to 50.0 micrograms per hour per kilogram of bodyweight of the mammal. The drug delivery system may comprise a transdermal patch loaded with the pharmaceutical agent. The patch may include a porous membrane and an outer impermeable cover defining a cavity therebetween. A plurality of drug delivery layers may be disposed between the porous membrane and the impermeable cover. A lipophilic/hydrophilic suspension may be disposed between the drug delivery layers.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 62/384,708, filed Sep. 7, 2016, U.S. Provisional Application Ser.No. 62/397,804, filed Sep. 21, 2016, and U.S. Provisional ApplicationSer. No. 62/489,555, filed Apr. 25, 2017, which applications areincorporated herein by reference in their entirety.

BACKGROUND

The present invention relates to transdermal delivery of pharmaceuticalagents, more particularly to a transdermal patch for administeringbiologically active compounds, such as but without limitation, apharmaceutical mixture of a liposomal prostaglandin, prostaglandinderivative, prostaglandin prodrug, or mixture thereof, cannabis THC,cannabinols, prostaglandins and other lipophilic fatty acids, throughthe skin of a mammal.

Transdermal drug delivery has become a common method of administering adrug or pharmaceutical agent. Transdermal patches are typically used toadminister a drug through the skin of a patient at a controlled rate.Matrix type transdermal patches not only carry the pharmaceutical agentbut also attach the patch to the skin of the patient. An adhesive matrixtype transdermal patch typically includes an impermeable backing, anadhesive layer and a removable protective liner. Pharmaceutical agentsmay be mixed in the adhesive layer and the patch applied to the skin ofa patient to deliver a dose of a pharmaceutical agent through the skinand into the bloodstream of the patient.

Prostaglandins are cyclic, oxygenated fatty acids known to be potentpharmacological agents and to have a potent effect on cell function inmany organ systems. Prostaglandin E1 (PGE1), for example, has variouspharmacological properties, the most notable being vasodilation,inhibition of platelet aggregation, and stimulation of intestinal anduterine smooth muscle. Major disadvantages of PGE1, however, are itsshort in-vivo half-life of approximately 30 to 90 seconds, instability,and rapid degradation. When administered intravenously, PGE1 is rapidlymetabolized during circulation through the lungs so that itspharmacological effects are significantly diminished by the time itreaches a target site or organ system.

Encapsulation of PGE1 in liposomes solves the problems of instability,short term half-line and rapid degradation experienced with PGE1 in itsfree form. Liposomes may function as sustained release systems fordrugs, and the rate of release may be manipulated. A liposomalformulation of pharmaceutical agents results in a more effectivetargeted delivery, enabling delivery of the maximum patient tolerateddosage with fewer side effects.

Phytocannabinoids have efficacy in the treatment of various chronic painconditions with greatest promise as a therapeutic adjunct in treatingperipheral and central neuropathic pain and inflammation-mediatedchronic pain. However, the smoked route of administration and thepsychoactivity of THC, with associated concerns about abuse andlong-term cognitive adverse effects, continue to pose serious andsignificant barriers to obtaining benefit from cannabis among mostpatients and acceptability among health care professionals andregulatory agencies.

It is therefore an object of the present disclosure to provide methodsand a transdermal patch for the administration of a pharmaceuticalagent, such as, but without limitation, PGE1 in liposomal or raw form,cannabis THC, cannabinols, prostaglandins and other lipophilic fattyacids, in liposomal or raw form, through the skin and into thebloodstream of a patient.

SUMMARY

A method of administering a pharmaceutical agent to the circulatorysystem through the skin of a mammal may include the steps of loading apharmaceutical agent in a transdermal patch, applying the transdermalpatch to the skin of the mammal and releasing the pharmaceutical agentinto the circulatory system at a rate of at least 0.001 micrograms perhour up to 50.0 micrograms per hour per kilogram of bodyweight of themammal.

In one embodiment, a drug delivery system may comprise a transdermalpatch loaded with a pharmaceutical agent. The patch may include a porousmembrane and an outer impermeable cover defining a cavity therebetween.A plurality of drug delivery layers may be disposed between the porousmembrane and the impermeable cover. A lipophilic/hydrophilic suspensionmay be disposed between the drug delivery layers.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the manner in which the above recited features, advantages andobjects of the present invention are attained can be understood indetail, a more particular description of the invention brieflysummarized above, may be had by reference to the embodiments thereofwhich are illustrated in the appended drawing.

It is noted, however, that the appended drawing illustrates only atypical embodiment of this invention and is therefore not to beconsidered limiting of its scope, for the invention may admit to otherequally effective embodiments.

FIG. 1 is a fragmentary section view of a first embodiment of atransdermal drug delivery patch.

FIG. 2 is a partially broken away top plan view of a second embodimentof a transdermal drug delivery patch.

FIG. 3 is a section view taken along line 3-3 of FIG. 2.

FIG. 4 is a section view of third embodiment of a transdermal drugdelivery patch.

FIG. 5 is a section view of a fourth embodiment of a transdermal drugdelivery patch.

DETAILED DESCRIPTION

A transdermal drug delivery system for the administration of apharmaceutical agent may include a transdermal patch. For purposes ofillustration, but without limitation, a transdermal patch may include animpermeable backing, a drug delivery tape, an adhesive layer and aremovable protective liner. Pharmaceutical agents encapsulated in aparticulate drug carrier, such as liposomes, may be incorporated in thetransdermal patch by methods known in the art.

Liposomes may be made of any suitable phospholipid, sphingolipid,glycolipid, derived lipid, and the like. Examples of suitablephospholipids include phosphatidylcholine, phosphatidyl serine,phosphatidie acid, phosphatidyl glycerol, phosphatidyl ethanolamine,phosphatidyl inositol, sphingomyelin, dicetyl phosphate,lysophosphatidyl choline and mixtures thereof, as well as soybeanphospholipids, and egg yolk phospholipids. Suitable glycolipids includecerebroside, sulphur-containing lipids, ganglioside and the like.

Liposomes and lipospheres may be formed by any of the known methods forforming liposomes and may be loaded with prostaglandin according toknown procedures. Those skilled in the art will recognize that, inaddition to prostaglandin, the liposomes and lipospheres may be loadedwith many other drugs or agents.

A transdermal patch may be loaded with pharmaceutical agents including,but not limited to, cannabis THC, cannabinols, prostaglandins and otherlipophilic fatty acids, in liposomal or raw form, a liposomal mixture,micro particulate mixture and/or a mixture of both may carryprostaglandin, prostaglandin derivative, prostaglandin prodrug or amixture thereof, cannabis THC, cannabinols, and other lipophilic fattyacids, in liposomal or raw form. The pharmaceutical agents may becompounded and designed to be delivered through the skin of a mammal,such as but without limitation, a human patient, and released into thebloodstream for the treatment of, but without limitation, cardiovasculardiseases, restenosis after angioplasty, occlusive peripheral andcoronary artery disease, liver disease, myocardial infarction, strokeand the like.

Referring now to FIG. 1, a transdermal drug delivery system may includea trasdermal patch generally identified by the reference numeral 100.The patch 100 may include a cavity 110 defined between a porous membrane112 and an outer impermeable skin or cover 114. The porous membrane 112may include a plurality of apertures 113. A layer 116 of a semi-porousadhesive may applied to a bottom surface of the membrane 112 forsecuring the patch 100 to the skin of a patient. A peel away liner 118may cover the adhesive layer 116. The liner 118 may be removed prior toapplication of the patch 100, thereby exposing the adhesive layer 116for securing the patch 100 to the skin of the patient.

One or more drug delivery layers for dispensing a pharmaceutical agentmay be disposed in the cavity 110. The drug deliver layers may compriseone or drug delivery tapes disposed in the patch cavity 110 verticallyspaced from one another. The patch 100 illustrated in FIG. 1, mayinclude an innermost drug delivery tape 120, a secondary drug deliverytape 122, a tertiary drug delivery tape 124 and a quaternary drugdelivery tape 126. Each drug delivery tape 120, 122, 124, 126 mayinclude a plurality of micro-dots 128 of pharmaceutical agentsincluding, but not limited to, cannabis THC, cannabinols, and otherlipophilic fatty acids, a liposomal mixture, micro particulate mixtureand/or a mixture of both carrying prostaglandin, prostaglandinderivative, prostaglandin prodrug or a mixture thereof, in liposomal orraw form, printed on the drug releasing tapes 120, 122, 124, 126.

A layer 130 of a lipophilic/hydrophilic suspension gel may be disposedbetween each of the drug releasing tapes 120, 122, 124, 126. Abiocompatible membrane 132 may overlay the drug releasing tapes 120,122, 124, 126. The outer impermeable skin or cover 114 may be appliedover the membrane 132.

In a preferred embodiment, the transdermal patch 100 may release atleast 0.001 micrograms per hour up to 50.0 micrograms per hour of apharmaceutical agent and/or mixture thereof per one kilogram ofbodyweight of the patient. More preferably, the transdermal patch 100may release 20 micrograms per hour of the pharmaceutical agent and/ormixture thereof per kilogram bodyweight. Prostaglandins or derivativesthereof may achieve a percent (%) weight to body weight ratio of drug toblood chemistry of at least 0.001% micrograms per one kilogram ofbodyweight of the patient and maintain a constant level of optimal bloodcirculation concentrations of up to 12 hours to 48 hours.

Referring now to FIGS. 2 and 3, a second embodiment of a transdermalpatch is generally identified by the reference numeral 200. Thetransdermal patch 200 may include a biocompatible membrane 210 coveredby an impermeable cover 212. The outer dimensions of the cover 212 mayextend beyond the perimeter of the membrane 210 and define a surface 214surrounding the membrane 210. A layer of adhesive may be applied to thesurface 214.

An array of polymer or micro needles 216 may be fixed to the membrane210 in a manner known in the art. The micro needles 216 may be hollowand loaded with an appropriate dosage of pharmaceutical agents,including but not limited to, a prodrug or derivative of prostaglandin.Each micro needle 216 may contain the precise dosage required forattaining and maintaining the pharmacological levels required by thepatient. A peel away liner 218 (not shown in the drawings) may extendover the tips of the micro needles 216. The liner 218 may be removedprior to application of the patch 200, thereby exposing the microneedles 216 for injection of the pharmaceutical agent into thecirculatory system of the patient.

Referring now to FIG. 4, a third embodiment of a transdermal patch isgenerally identified by the reference numeral 300. The patch 300 mayinclude an impermeable cover 310. Raw or generic prostaglandin (PGE1)may be loaded in an adhesive layer 312 applied to one side of the cover310. The PGE1 may be mixed with the adhesive and/or a binder. The PGE1may be released over a period of time by body heat melting thin layersof the PGE1 embedded in the adhesive layer 312.

A fourth embodiment of a transdermal patch, shown in FIG. 5, isgenerally identified by the reference numeral 400. The patch 400 mayinclude am impermeable cover 410 configured to define a void orreservoir 412. The cover 410 may include a radially outwardly extendingportion 414 circumscribing the reservoir 412. Adhesive may be applied tothe bottom surface of the cover portion 414 for adhesively securing aporous membrane 416 covering the reservoir 412 to the cover 410. A peelaway liner 418 releaseably attached to the membrane 416 may be removedprior to securing the patch 400 to the skin of a patient. The patch 400may provide controlled release of raw PGE1 contained in the reservoir412 through the porous membrane 412 covering the reservoir 412.

While preferred embodiments of a transdermal patch have been shown anddescribed, other and further embodiments may be devised withoutdeparting from the basic scope thereof, and the scope thereof isdetermined by the claims which follow.

The invention claimed is:
 1. A drug delivery system comprising: a) atransdermal patch for administering a pharmaceutical agent through theskin of a patient; b) said patch including a porous membrane and anouter impermeable cover defining a cavity therebetween; c) a layer ofsemi-porous adhesive applied to a bottom surface of said porousmembrane; d) a plurality of drug delivery tapes disposed in said cavityin vertical spaced layers relative to one another; e) a plurality ofmicro-dots containing said pharmaceutical agent imprinted on each saidplurality of drug delivery tapes; and f) a layer of lipophilic orhydrophilic suspension disposed between said layers of said plurality ofdrug delivery tapes.
 2. The drug delivery system of claim 1 wherein saidpharmaceutical agent is released at a rate of at least 0.001 microgramsper hour up to 50.0 micrograms per hour per kilogram of bodyweight ofthe patient.
 3. The drug delivery system of claim 1 wherein saidpharmaceutical agent is released at a rate of 20 micrograms per hour perkilogram bodyweight of the patient.
 4. The drug delivery system of claim1 wherein said porous membrane includes a plurality of apertures.
 5. Thedrug delivery system of claim 1 wherein said pharmaceutical agentcomprises cannabis THC.
 6. The drug delivery system of claim 1 whereinsaid pharmaceutical agent comprises cannabinols.
 7. The drug deliverysystem of claim 1 wherein said pharmaceutical agent comprises aliposomal prostaglandin, prostaglandin derivative, prostaglandinprodrug, or mixture thereof.
 8. The drug delivery system of claim 1wherein said pharmaceutical agent comprises a lipophilic fatty acid. 9.The drug delivery system of claim 1 further including a biocompatiblemembrane overlaying said plurality of drug delivery tapes.
 10. The drugdelivery system of claim 1 further including a removable lineroverlaying said semi-porous adhesive layer.
 11. The drug delivery systemof claim 9 wherein said pharmaceutical agent comprises a liposomalprostaglandin, prostaglandin derivative, prostaglandin prodrug, ormixture thereof.
 12. The delivery system of claim 9 wherein saidpharmaceutical agent comprises cannabis THC, cannabinols, orprostaglandins in liposomal or raw form.